Ichthyosis and erythrokeratoderma

Gene: GJA1

The mode of inheritance of this gene has been updated to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 2:33 p.m. | Last Modified: 31 Jan 2023, 2:33 p.m.

Panel Version: 2.12

Comment on mode of inheritance: MOI should be changed from 'both mono- and biallelic' to 'monoallelic' only at the next GMS panel update.

GJA1 was imported to this panel from the 'Palmoplantar keratoderma and erythrokeratodermas' 100K panel and the MOI reflects the mixed inheritance pattern associated with GJA1 oculodentodigital dysplasia (ODDD) (dominant - MIM:164200; recessive - MIM:257850) which can manifest with PPK. Following the uncoupling of PPK and erythrokeratodermas into two separate GMS panels (R165 & R166), only monoallelic variants remain relevant to this particular panel.

Monoallelic variants can cause erythrokeratodermia variabilis et progressiva 3 (MIM: 617525). Erythematous palms and soles have also been described in cases of GJA1-related palmoplantar keratoderma (MIM:104100), also associated with heterozygous variants.

Created: 31 Aug 2021, 2:14 p.m. | Last Modified: 31 Aug 2021, 3:44 p.m.

Panel Version: 1.66

Comment on phenotypes: Previous phenotypes:
keratoderma, hypotrichosis and leukonychia;Palmoplantar keratoderma with congenital alopecia, 104100;Erythrokeratoderma;Erythrokeratodermia variabilis et progressiva 3, 617525;Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma;Palmoplantar keratoderma

Created: 23 Mar 2021, 2:18 p.m. | Last Modified: 23 Mar 2021, 2:18 p.m.

Panel Version: 1.26

Comment on phenotypes: Removed phenotype 'Erythrokeratodermia variabilis et progressiva, 133200' because a June 2017 OMIM update now associates GJA1 with 'Erythrokeratodermia variabilis et progressiva 3, 617525'.

Created: 15 Aug 2017, 2:23 p.m.

Comment when marking as ready: Expert review Green. >3 cases from OMIM and literature supporting causation.

Created: 16 Mar 2017, 10:05 a.m.

Comment on mode of pathogenicity: PMID:16891658 (Gong et al., 2006) perform functional studies that suggest that frameshfit mutation fs260 (780-781del) dominantly negatively inhibits the wildtype protein.

Created: 16 Mar 2017, 10:03 a.m.

Comment on list classification: Updated rating from Amber to Green: 1 Green expert review. At least 3 disorders resulting from GJA1 mutations are relevant to this panel: PPK with congenital alopecia, 104100, Oculodentodigital dysplasia (ODDD, MIM:164200 and MIM:257850), and Erythrokeratodermia variabilis et progressiva (MIM:133200). Confirmed G2P gene for ODDD disorders, and >3 cases supporting causation for a PPK phenotype.

Created: 16 Mar 2017, 9:57 a.m.

Edel O'Toole provided publications (PMID:25388818, PMID:17256797) reporting oculodentodigital dysplasia (ODDD) patients with palmoplantar keratoderma (PPK). PPK is a minor symptom in patients with Oculodentodigital dysplasia (ODDD), and may be limited to specific mutations of GJA1.

Created: 16 Mar 2017, 9:55 a.m.

Comment on mode of inheritance: Reverted MOI back to 'both monoallelic and biallelic' based on reviewer recommendation. Oculodentodigital dysplasia (ODDD), which can present with PPK, is caused by mutations in GJA1, and can be dominantly (MIM:164200) or recessively (MIM:257850) inherited.

Created: 16 Mar 2017, 9:52 a.m.

Comment on list classification: Updated rating from Red to Amber ready for Expert review. >3 unrelated cases supporting the link between GJA1 and Palmoplantar keratoderma (OMIM:104100) or EKVP (OMIM:133200).

Created: 10 Jan 2017, 3:25 p.m.

Comment on mode of inheritance: Updated mode of inheritance from 'Both monoallelic and biallelic' to just monoallelic. Although OMIM report both biallelic and monoallelic causes of EKVP (OMIM:133200) for GJA1, GJB3 and GJB4, for GJA1 the literature reports heterozygous (monoallelic) mutations (PMID:25398053). Rare biallelic forms of EKVP (OMIM:133200) have so far just been reported for GJB3.

Created: 10 Jan 2017, 3:23 p.m.

Two GJA1 variants are recorded for 3 unrelated individuals with EKVP (OMIM:133200) by Boyden et al., 2015 (PMID:25398053). The same heterozygous missense mutation (E227D) is reported in a 32-month old boy (origin not specified) and a 6 year old girl (from Guatemala). Another heterozygous GJA1 mutation, A44V, was found in a third affected subject, a 30-year old woman (origin not specified). Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma (PMID:25398053).

Created: 9 Jan 2017, 11:11 a.m.

In 3 patients from 2 Chinese families (an affected father and daughter, and an unrelated Chinese boy) with 'palmoplantar keratoderma and congenital alopecia-1' (PPKCA1; 104100), Wang et al. (2015, PMID:25168385) identified heterozygosity for a c.23G-T missense mutation in the GJA1 gene resulting in a G8V substitution. Patch-clamp studies in transfected HEK293 cells demonstrated a gain-of-function effect.

Created: 9 Jan 2017, 11:10 a.m.

Comment on mode of inheritance: Mode of inheritance sourced from OMIM: monoallelic mutations in GJA1 are recorded for 'Palmoplantar keratoderma with congenital alopecia' (OMIM:104100). Both monoallelic and biallelic mutations in GJA1 are recorded for 'Erythrokeratodermia variabilis et progressiva' (OMIM:133200).

Created: 5 Jan 2017, 12:50 p.m.

Green List (high evidence)

Missense mutations, frame-shift and C-terminal truncation reported

Created: 14 Mar 2017, 7 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia; keratoderma, hypotrichosis and leukonychia

Publications

• 25398053
• 25388818
• 25168385
• 17256797
• 16891658

Mode of pathogenicity
Other